Gulf War Veterans' Illness: Symptom Chronicity via Interactions of Diet andLifestyle Risk Factors with the Gut Microbiome

项目总结/摘要 海湾战争退伍军人疾病（GWVI）表现为多种症状的复杂星座， 在海湾战争退伍军人被部署到海湾地区25年多后，这套 症状是如此广泛，它阻碍了诊断标准，因此，考虑GWVI作为一个真正的疾病 从否认其存在到使用诸如“不明原因的疾病”（由 “多症状疾病”（multisymptoms illness）。医学研究所海湾战争委员会的最新报告 和健康（2016）得出结论，GWVI不是一种心身疾病，现在有足够的证据表明， 结论是，被部署到海湾战争和健康结果之间存在因果关系 与这种疾病有关。这个庄严的委员会注意到，在阐明 与GWVI相关的复杂症状集的病理机制，因此，“它 似乎没有一个单一的机制可以解释海湾战争疾病的众多症状， 战后这么多年，不太可能确定一个确定的致病因素”（报告第3页）。 我们同意GWVI的所有因素不太可能是单一原因，可能是单一的病理生理学原因。 机制，可以影响GWVI的各种症状，并解释其持久性， 其机制是肠道微生物组的生态失调。该项目的主要目标是分析 海湾战争的代理人对肠道细菌的影响，并确定这些相互作用是否会导致 短链脂肪酸（SCFAs）和其他生物活性小分子的细菌生产的变化 由肠道细菌产生。这些细菌发酵和代谢的产物发挥许多作用 包括中枢神经系统。将用经验证的GWVI小鼠模型治疗小鼠 （溴化吡啶斯的明+氯菊酯），并将通过16 S rRNA测序分析肠道微生物组 使用MiSeq平台。这些相同的试剂对SCFA产生的影响将使用 液相色谱-质谱法确认为GWVI症状的CNS和GI疾病将 也要评估。此后，高脂肪饮食对微生物组和SCFA产生的影响将被 评估。最后，提出了一个新的治疗目标，将测试饮食干预和粪便微生物群 转移，因为它们能够恢复GWVI修饰的肠道微生物组的平衡并减少CNS， 这种严重疾病的胃肠道症状。据预测，高脂肪的饮食将扩大海湾战争的影响 药物对微生物组和代谢组的影响，并导致GWVI症状的时间依赖性恶化。 下一代测序和尖端质谱技术的应用将有助于填补空白 我们对海湾战争特工如何影响沟通沿着内脏-大脑轴的理解。这些研究 也可能揭示新的治疗目标GWVI通过恢复平衡肠道微生物组通过饮食 和微生物群转移干预。

Project Summary/Abstract Gulf War Veterans’ Illnesses (GWVI) presents as a complex constellation of diverse symptoms that have persisted in Gulf War Veterans more than 25 years after their deployment to the Gulf region. This set of symptoms is so broad, it baffles diagnostic criteria and as a result, consideration of GWVI as a bona fide illness has progressed slowly from denial of its existence to the use of such terms as “unexplained illnesses” (used by the VA) and “multisymptom illness”. The most recent report by the Institute of Medicine Committee on Gulf War and Health (2016) concludes that GWVI is not a psychosomatic condition and sufficient evidence now exists to conclude that a causal relationship exists between being deployed to the Gulf War and the health outcomes associated with this disorder. This august Committee noted that little progress has been made in elucidating the pathological mechanisms that underlie the complex symptom set associated with GWVI and as a result, “it does not appear that a single mechanism can explain the multitude of symptoms seen in Gulf War Illness, and it is unlikely that a single definitive causal agent will be identified this many years after the war” (p. 3 of report). We agree that a single cause for all elements of GWVI is unlikely, it is possible that a single pathophysiological mechanism that could influence the diverse symptoms of GWVI, and explain their persistence, and that mechanism is a dysbiosis in the gut microbiome. The broad objectives of this project are to analyze the effects of Gulf War agents on the commensal bacteria in the gut and to determine if these interactions result in changes in the bacterial production of short chain fatty acids (SCFAs) and other bioactive small molecules produced by gut bacteria. These products of bacterial fermentation and metabolism exert numerous effects throughout the body to include the CNS. Mice will be treated with a validated mouse model of GWVI (pyridostigmine bromide plus permethrin) and the gut microbiome will be analyzed via 16S rRNA sequencing using the MiSeq platform. The effects of these same agents on SCFA production will be determined using liquid chromatography-mass spectrometry. CNS and GI disorders that are confirmed symptoms of GWVI will also be assessed. Thereafter, the effects of a high fat diet on the microbiome and SCFA production will be evaluated. Finally, a new treatment aim is proposed that will test dietary intervention and fecal microbiota transfer for their ability to restore balance in the GWVI-modified gut microbiome and to diminish the CNS and GI symptoms of this serious disorder. It is predicted that a high fat diet will magnify the effects of Gulf War agents on the microbiome and the metabolome and cause a time-dependent worsening of GWVI symptoms. Together, the application of next generation sequencing and cutting edge mass spectrometry will help fill gaps in our understanding of how Gulf War agents influence communication along the gut-brain axis. These studies may also reveal new therapeutic targets for GWVI by restoring balance in the gut microbiome through dietary and microbiota transfer interventions.